Several publications are referenced in this application by author name and year of publication in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
Apoptosis is a genetically controlled pathway of programmed cell death. The hallmarks of apoptosis are cytoplasmic boiling, chromatin condensation, and DNA fragmentation. Apoptosis plays a major role in development and disease. Regulation of cell death is essential for normal development and is an important defense against viral infection and the emergence of cancer. Excessive cell death can lead to impaired development and degenerative diseases, whereas too little cell death can lead to cancer and persistent and sustained viral infection.
Tumor suppressor genes are a class of genes involved in different aspects of normal control of cellular growth and division. Inactivation of tumor suppressor genes, usually by genetic means, contributes to tumor development. The first evidence for the existence of such genes came from the observation that fusion of normal cells with tumor cells resulted in hybrids which were nontumorigenic. However, with the loss of chromosomes, which occurs naturally when hybrid cells are grown in culture, the tumorigenic phenotype was sometimes restored. Furthermore, the introduction of normal chromosomes into tumorigenic hybrids can cause reversal to the nontumorigenic phenotype. Thus expression of genes from the normal parent suppresses tumorigenicity.
As the normal functioning of tumor suppressor genes suppresses tumorigenicity, regions of chromosomes which are lost in tumors are likely to carry tumor suppressor genes. Karyotype analysis of a wide variety of tumor types has shown that certain chromosomal deletions occur with a high frequency and in a tumor specific manner, thus implicating the chromosomal region as a likely location of tumor suppressor genes.
Apoptosis is controlled through the expression of an increasing number of genes conserved in nematodes through mammals and viruses. Some gene products are activators of apoptosis, whereas others are inhibitors. Tumor suppressor genes are also widely conserved. The characterization of the function of these gene products will facilitate elucidation of the molecular mechanisms which regulate cell growth at the biochemical level. This knowledge in turn, facilitates the identification and characterization of agents suitable for regulating apoptotic cell death and tumor suppression which may be used to advantage in the treatment of malignancy and other disorders characterized by aberrant cell growth.